CN102731458A - Bi-isopentene coumarin, as well as preparation method and application thereof - Google Patents
Bi-isopentene coumarin, as well as preparation method and application thereof Download PDFInfo
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- CN102731458A CN102731458A CN201210242294XA CN201210242294A CN102731458A CN 102731458 A CN102731458 A CN 102731458A CN 201210242294X A CN201210242294X A CN 201210242294XA CN 201210242294 A CN201210242294 A CN 201210242294A CN 102731458 A CN102731458 A CN 102731458A
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Abstract
The invention discloses bi-isopentene coumarin, as well as a preparation method and application thereof. A new compound is separated from Micromelum falcatum, and is bi-isopentene coumarin shown in a formula (I). The LD50 (median lethal dose) value of the compound to artemia is 25.5mu g/mL, the anti-adhesion activity concentration IC50 (half maximal inhibitory concentration) of the compound to kentrogon is 6.77mu g/mL, and the half maximal inhibitory concentration IC50 of the compound to lung cancer cells HvEvc is 76.4mu g/mL. Therefore, the compound can be used for preparing an anti-artemia medicament, a fouling organism larva adhesion prevention medicament and an anti-tumor medicament or used as a leading compound, and has wide application prospect.
Description
Technical field:
The invention belongs to the natural product field, be specifically related to two isopentene group tonka bean camphors and preparation method thereof and adhere to the application aspect the medicine the biological larva of preparation cancer therapy drug, anti-halogen worm medicine and fouling resistance.
Background technology:
The Rutaceae Root of Entire Micromelum belongs in the bassoon (Micromelum falcatum) once separating and obtains vegeto-alkali yuehchukene and 5,6-pyranoglycozoline, tonka bean camphor micromelin, compounds such as phebalosin and murpanidin.(reference: Kong YC, But PPH, Ng KH, Li Q, Cheng KF, Waterman PG, Biochem.Syst.Ecol., 1988,16:485).
Summary of the invention:
First purpose of the present invention provides one to be had the biological larva of anticancer, anti-halogen worm and fouling resistance and adheres to active pair of isopentene group tonka bean camphor or its salt.
Of the present invention pair of isopentene group tonka bean camphor or its salt, its structural formula is suc as formula shown in (I):
Second purpose of the present invention provides the preparation method suc as formula the two isopentene group tonka bean camphors shown in (I), it is characterized in that, bassoon (Micromelum falcatum) is shredded; With ethanol or aqueous ethanolic solution lixiviate, vat liquor concentrates and obtains crude extract, and crude extract is suspended in water; Use ethyl acetate extraction, ETHYLE ACETATE concentrate mutually acetic acid ethyl ester extract, the acetic acid ethyl ester extract that obtains is carried out silica gel column chromatography; As eluent, carry out gradient elution with sherwood oil/acetone from volume ratio 9:1 to 3:7, with the cut point plate of wash-out under the volume ratio 6:4 gradient; Carry out thin-layer chromatography; The chloroform/acetone solvent systems that with the volume ratio is 9:1 is as developping agent, is that 0.3 cut merges with Rf value, sloughs pigment and promptly gets the two isopentene group tonka bean camphors suc as formula (I) expression.
Described concentrate can adopt conventional method to concentrate, for example concentrating under reduced pressure etc.
The described pigment of sloughing can adopt conventional method such as gel chromatographic columns to slough pigment etc., preferably through gel filtration chromatography, is that eluent is sloughed pigment with methyl alcohol.
The present invention finds through experiment, suc as formula the LD of the two isopentene group tonka bean camphors shown in (I) to the halogen worm
50Value is 25.5 μ g/mL; The anti-active concentration IC that adheres to kentrogon
50Be respectively 6.77 μ g/mL; Average half inhibiting rate IC to lung carcinoma cell HvEvc
50Be 76.4 μ g/mL.
Therefore the 3rd purpose of the present invention provides suc as formula two isopentene group tonka bean camphors shown in (I) or the application of its salt in the anti-halogen worm medicine of preparation.
The 4th purpose of the present invention provides suc as formula the two isopentene group tonka bean camphors shown in (I) adheres to the application in the medicine the biological larva of preparation fouling resistance.
Described fouling organism larva is preferably kentrogon.
The 5th purpose of the present invention provides suc as formula the application of the two isopentene group tonka bean camphors shown in (I) in the preparation antitumor drug.
Described antitumor drug is preferably anti-lung-cancer medicament.
The present invention separates from bassoon (Micromelum falcatum) and obtains a new compound suc as formula the two isopentene group tonka bean camphors shown in (I), and this compound is to the LD of halogen worm
50Value is 25.5 μ g/mL, to the anti-active concentration IC that adheres to of kentrogon
50Be 6.77 μ g/mL; Average half inhibiting rate IC to lung carcinoma cell HvEvc
50Therefore be 76.4 μ g/mL, can this compound be used to prepare anti-halogen worm medicine, the biological larva of fouling resistance and adhere to medicine and antitumor drug or, have broad application prospects as lead compound.
Embodiment:
Following examples are to further specify of the present invention, rather than limitation of the present invention.
Embodiment 1: the separation of two isopentene group tonka bean camphors and structure are identified
With 10kg bassoon branch is raw material, and the chopping back with the extracting solution concentrating under reduced pressure, gets crude extract with the aqueous ethanolic solution lixiviate of volume(tric)fraction 95%.Be dissolved in the 2000mL water crude extract is outstanding, extract 4 times with isopyknic ETHYLE ACETATE 2000mL, the combining extraction liquid concentrating under reduced pressure obtains acetic acid ethyl ester extract 113g; Acetic acid ethyl ester extract is carried out normal pressure silica gel column chromatography (high 1.5m, the glass column of diameter 10cm, silica gel 200 ~ 300 orders); With sherwood oil/acetone solvent system is elutriant; Carrying out gradient elution from volume ratio 9:1 to 3:7, is the cut point plate of 6:4 gradient elution with volume ratio, carries out TLC (GF
254) analyze, be that the chloroform/acetone solvent systems of 9:1 is a developping solution with the volume ratio, with R
fValue is 0.30 cut merging, and last Sephadex LH-20 gel filtration chromatography is elutriant flushing (high 1.0m, the glass column of diameter 3cm, pure methanol-eluted fractions) with depigmentation with methyl alcohol, obtains compound 1 7.2mg altogether.
Compound 1: outward appearance is a colorless oil.High resolution mass spectrum HREI-MS m/z 374.1728 (C
21H
26O
6 +[M]
+, calculated value: 374.1724).Its hydrogen spectrum (
1H-NMR) data and carbon the spectrum (
13C-NMR) data are seen table 1, and these data all are to be interior mark with TMS (TMS), on the NMR of 500MHz and 125MHz, measure respectively, and solvent all is CDCl
3, chemical shift is unit with ppm, coupling constant J, and unit is Hz.UV: 282.0,323.0nm shows to have 7-methyl substituted tonka bean camphor skeleton, infrared IR:3541,1739,1732,1604,1543,1450,1223cm
-1Show have phenyl ring, ester bond and hydroxyl.Through 8 tonka bean camphor groups that replace-7 methoxyl groups of the bright existence of a peacekeeping two-dimensional data table in the analytical table 1, an isopentene group and a △
1'-4 ', 5 '-dioxygen replacement isopentene group.COSY composes relevant H-4 " (δ 0.95)/H-3 " (the δ 2.11)/H-2 that shows, and " (δ 2.25) are relevant.The bright H-2 of HMBC stave " with C-1 " (δ 173.2), C-3 " (δ 25.6), C-4 " (δ 22.1) and C-5 " (δ 22.1) is relevant, H-3 " with C-1 ", C-2 " (δ 43.4), C-4 " with C-5 " is relevant, H-4 " with C-2 ", C-3 " with C-5 " is relevant, has proved to have isopentene group.The COSY composes H-1 ' (δ 6.92)/H-2 ' (δ 6.67), H-2 '/H-3 ' (δ 2.85), and H-3 '/H-4 ' (δ 4.32) and H-3 '/H-5 ' (δ 3.76) have proved △
1'-4 ', 5 '-dioxygen replacement isopentene group.HMBC spectrum H-4 '/C-1 " (δ 173.2) relevant relevant with H-1 '/C-7/C-8/C-9 show that above three groups are through C-1 "/C-4 ' ester bond and C-1 '/C-8 carbon-carbon bond link, and HMBC composes δ
H3.92 (3H, s) and C-7 (δ 160.6) prove methoxyl group on C-7, HMBC composes δ
H3.56 (3H, s) and C-5 ' (δ 63.4) prove methoxyl group on C-5 ', between H-1 ' and H-2 ' coupling constant 16.4Hz shows that C-1 ' and C-2 ' are trans.Therefore, compound 1 identifies that its structural formula is suc as formula shown in (I).
Table 1: the hydrogen spectrum of the described compound 1 of formula (I) and carbon spectrum data
Embodiment 2: the biological method that causes death of cytotoxic activity test-halogen worm
Get artemia cysts 150mg and place the 500mL beaker, add artificial seawater 500mL, slowly inflate with a little aerator pump, room temperature hatching 24h removes chorion and unhatched ovum, and halogen worm larva continues to cultivate 24h, and is subsequent use.
According to the improved method of Solis, get 96 porocyte culture plates, every hole adds the artificial seawater liquid that 200 μ L contain 10 ~ 15 halogen worm larvas, processes the test cultures plate.A blank group and sample sets are set; Wherein establish three parallel holes for every group, add 5 μ L dimethyl sulphoxide solutions (DMSO) in the blank group, sample sets adds compound 1 solution that the embodiment 1 of 5 μ L obtains and (compound 1 is used dmso solution; Be mixed with different concns); The compound final concentration of three parallel holes is respectively 500 μ g/mL, 50 μ g/mL, 5 μ g/mL in the sample sets that makes, and behind the incubated at room temperature 24h, under the binocular anatomical lens, detects the dead individual number of counting halogen worm.The biological activity that causes death of halogen worm is represented with corrected mortality, calculates by following formula: corrected mortality=(control group survival rate-treatment group survival rate)/control group survival rate * 100%.And corrected mortality imported the SPSS software for calculation, calculate LC
50The result draws, the average LD of compound 1
50Value is 25.5 μ g/mL.
Embodiment 3: the activity test of the anti-breast cancer of tetrazolium bromide (MTT) method test compounds 1
Collect breast cancer cell (F10), inoculate 100 μ L in 96 orifice plates, every porocyte number is approximately 1.0 * 10
5Individual, orifice plate is put into CO
2In the incubator, 37 ℃, 5%CO
2The conventional cultivation 24 hours.Add 10 times of dilutions, the solution of the compound 1 that embodiment 1 obtains (compound 1 use dmso solution, be mixed with 20mg/mL) 100 μ L, get 3 parallel, conventional cultivation 24 hours, negative control does not add medicine.Sucking-off nutrient solution again, the MTT50 μ L that every hole adds complete substratum 150 μ L and concentration 2mg/mL cultivates sucking-off liquid after 4 hours, adds DMSO150 μ L, and vibration 10min, ELIASA 490nm measure the result down.Calculate inhibitory rate of cell growth, calculation formula is following: growth inhibition ratio (%)=[(A
Negative-A
Test)/(A
Negative-A
Blank)] * 100%.Utilize the SPSS computed in software again, draw the average half inhibiting rate IC of structural formula suc as formula the 1 pair of breast cancer cell of compound shown in (I)
50For greater than 200 μ g/mL, show obviously activity of nothing.
The anti-lung cancer activity test of embodiment 4:MTT method test compounds 1
Collect lung carcinoma cell HvEvc, inoculate 100 μ L in 96 orifice plates, every porocyte number is approximately 1.0 * 10
5Individual, orifice plate is put into CO
2In the incubator, 37 ℃, 5%CO
2The conventional cultivation 24 hours.Add 10 times of dilutions, the solution of the compound 1 that embodiment 1 obtains (compound 1 use dmso solution, be mixed with 20mg/mL) 100 μ L, get 3 parallel, conventional cultivation 24 hours, negative control does not add medicine.Sucking-off nutrient solution again, the MTT50 μ L that every hole adds complete substratum 150 μ L and concentration 2mg/mL cultivates sucking-off liquid after 4 hours, adds DMSO150 μ L, and vibration 10min, ELIASA 490nm measure the result down.Method according to embodiment 3 is calculated inhibitory rate of cell growth, utilizes the SPSS computed in software again, draws the average half inhibiting rate IC of structural formula suc as formula 1 pair of lung carcinoma cell of compound of (I) expression
50Be 76.4 μ g/mL, have certain cytotoxic activity.
Embodiment 5: the biological larva of fouling resistance adhere to activity
The anti-kentrogon of adopting 24 orifice plates mensuration embodiment 1 to obtain compound 1 adheres to activity.
Each is cultivated and adds the nutrient solution that 1mL contains 10 ~ 15 sophisticated kentrogons in the plate hole; The compound 1 that embodiment 1 is obtained is dissolved in DMSO; Join then in the nutrient solution that contains 10 ~ 15 sophisticated kentrogons of cultivating plate hole; Make the final concentration of compound 1 be respectively 100 μ g/mL, 10 μ g/mL, 1.0 μ g/mL and 0.1 μ g/mL, 3 of each concentration are parallel, and do blank with aseptic seawater.Culture plate is placed conventional the cultivation 24 hours under the room temperature, and the larva number that statistics is adhered under anatomical lens carries out statistical study with the SPSS program.Statistical result showed, the compound 1 average adhesive rate to kentrogon when concentration 100 μ g/mL, 10 μ g/mL, 1.0 μ g/mL and 0.1 μ g/mL is respectively 11.4%, 22.3%, 46.5%, 57.1%; The blank group is 62.9% to the average adhesive rate of kentrogon.The anti-larva that adheres to the formula computerized compound 1 of inhibiting rate=(blank-adhesive rate)/blank * 100% according to larva adheres to activity, and the anti-kentrogon that draws compound 1 adheres to active concentration IC
50Be 6.77 μ g/mL, explain that thus compound 1 has the biological larva of fouling resistance and adheres to activity.
Claims (9)
1. two isopentene group tonka bean camphors or its salt of following formula (I) expression:
2. the preparation method of described pair of isopentene group tonka bean camphor of a claim 1 is characterized in that, bassoon (Micromelum falcatum) is shredded; With ethanol or aqueous ethanolic solution lixiviate, vat liquor concentrates and obtains crude extract, and crude extract is suspended in water; Use ethyl acetate extraction, ETHYLE ACETATE concentrate mutually acetic acid ethyl ester extract, the acetic acid ethyl ester extract that obtains is carried out silica gel column chromatography; As eluent, carry out gradient elution with sherwood oil/acetone from volume ratio 9:1 to 3:7, with the cut point plate of wash-out under the volume ratio 6:4 gradient; Carry out thin-layer chromatography; The chloroform/acetone solvent systems that with the volume ratio is 9:1 is as developping agent, is that 0.3 cut merges with Rf value, sloughs pigment and promptly gets the two isopentene group tonka bean camphors suc as formula (I) expression.
3. preparation method according to claim 2 is characterized in that, described simmer down to concentrating under reduced pressure.
4. according to claim 2 or 3 described preparing methods, it is characterized in that the described pigment of sloughing is through gel filtration chromatography, is that eluent is sloughed pigment with methyl alcohol.
5. described pair of isopentene group tonka bean camphor of claim 1 or its salt application in the anti-halogen worm medicine of preparation.
6. described pair of isopentene group tonka bean camphor of claim 1 or its salt adhere to the application in the medicine the biological larva of preparation fouling resistance.
7. application according to claim 6 is characterized in that, described fouling organism larva is a kentrogon.
8. described pair of isopentene group tonka bean camphor of claim 1 or its salt application in the preparation antitumor drug.
9. application according to claim 8 is characterized in that, described antitumor drug is an anti-lung-cancer medicament.
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Cited By (3)
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| CN103992240A (en) * | 2014-04-24 | 2014-08-20 | 中国科学院南海海洋研究所 | Micrometams and application thereof |
| CN110078720A (en) * | 2019-05-28 | 2019-08-02 | 扬州工业职业技术学院 | Halogenated benzofuran-coumarin derivative and its preparing the application in fouling resistance agent |
| CN110105345A (en) * | 2019-05-28 | 2019-08-09 | 扬州工业职业技术学院 | The cumarin amine derivative and its application in fouling resistance that benzofuran replaces |
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| CN110105345A (en) * | 2019-05-28 | 2019-08-09 | 扬州工业职业技术学院 | The cumarin amine derivative and its application in fouling resistance that benzofuran replaces |
| CN110078720B (en) * | 2019-05-28 | 2020-07-17 | 扬州工业职业技术学院 | Halogenated benzofuran-coumarin derivative and application thereof in preparation of anti-fouling agent |
| CN110105345B (en) * | 2019-05-28 | 2020-07-17 | 扬州工业职业技术学院 | Benzofuran substituted coumarin amine derivative and application thereof in pollution resistance |
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Inventor after: Luo Xiongming Inventor after: Yin Hao Inventor after: Li Chuanrong Inventor after: Li Qingxin Inventor before: Luo Xiongming Inventor before: Zhang Cai Inventor before: Yin Hao Inventor before: Li Chuanrong Inventor before: Li Qingxin |
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Free format text: CORRECT: INVENTOR; FROM: LUO XIONGMING ZHANG SI YIN HAO LI CHUANRONG LI QINGXIN TO: LUO XIONGMING YIN HAO LI CHUANRONG LI QINGXIN |
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Granted publication date: 20140326 Termination date: 20200712 |